Major side effects and safety of calcium channel blockers

INTRODUCTION — Calcium channel blockers are widely used in the treatment of hypertension, angina pectoris, cardiac arrhythmias, and other disorders. The longer-acting preparations have been prescribed with increasing frequency. According to recommendations from the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the prevention, detection, evaluation, and treatment of high blood pressure, calcium channel blockers are a recommended choice for initial management of hypertension, either as monotherapy or as part of antihypertensive combination therapy. There are robust data suggesting that their use reduces the risk of subsequent cardiovascular events [1-3]. In addition, some meta-analyses have suggested that calcium channel blockers may be more effective than other drugs in reducing stroke risk [4-8]. (See "Choice of drug therapy in primary (essential) hypertension".)

A review of the major side effects associated with these agents and the controversy concerning their effect on coronary events, mortality, gastrointestinal bleeding, and the development of cancer are presented here. The management of calcium channel blocker intoxication is presented separately. (See "Calcium channel blocker poisoning".)

TYPES OF CALCIUM CHANNEL BLOCKERS — While all approved calcium channel blockers inhibit the L-type calcium channel on cells, they are divided into two major categories based upon their predominant physiologic effects: the dihydropyridines, which are predominantly vasodilators and generally have limited chronotropic and inotropic effects, and the non-dihydropyridines, which are less potent vasodilators and also slow cardiac contractility and conduction [9].

Dihydropyridines — The dihydropyridines, including nifedipine, isradipine, felodipine, nicardipine, nisoldipine, lacidipine, amlodipine, and levamlodipine are potent vasodilators that have little or no negative effect upon cardiac contractility or conduction. They are typically used to treat hypertension or chronic stable angina. Different agents and preparations have different durations of action. Longer-acting agents are generally safer and are increasingly preferred. These agents are preferred over the non-dihydropyridines for the treatment of hypertension [1].

Non-dihydropyridines — The non-dihydropyridines, including verapamil and diltiazem, are used in the management of hypertension, chronic stable angina, cardiac arrhythmias, or for proteinuria reduction. They are somewhat less potent vasodilators compared with dihydropyridines, but they have a greater depressive effect on cardiac conduction and contractility. (See "Calcium channel blockers in the treatment of cardiac arrhythmias" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Calcium channel blockers'.)

KNOWN SIDE EFFECTS

Overview of known adverse effects — The potential adverse effects that may be seen with calcium channel blockers vary with the type and dose:

●The dihydropyridines (eg, amlodipine, felodipine, nifedipine) may lead to headache, lightheadedness, flushing, and dose-dependent peripheral edema in as many as 20 to 30 percent of patients [10,11].

●The major potential adverse effects with the non-dihydropyridines (verapamil and diltiazem) are dose-dependent constipation, which may occur in as many as 25 percent of patients [12], as well as bradycardia and worsening cardiac output. Thus, these drugs are relatively contraindicated in patients who are taking beta blockers or who have heart failure with reduced ejection fraction (HFrEF), sick sinus syndrome, and second- or third-degree atrioventricular block.

●In addition, either dihydropyridines or non-dihydropyridines when used chronically can lead to gingival hyperplasia in some cases.

In general, most adverse effects of calcium channel blockers are dose dependent, so a decrease in dose is a possible way to improve tolerability. Patients who do not tolerate dihydropyridines may tolerate a change to non-dihydropyridines and vice versa. Non-dihydropyridines and, to a lesser extent, dihydropyridines are metabolized through the cytochrome P450 (CYP) 3A4 system (like some statins, azoles, protease inhibitors, and other drugs), and, as such, they should be used with caution in patients who are prescribed other agents that affect this metabolic pathway or who consume large amounts of grapefruit juice.

Edema — The peripheral edema associated with calcium channel blockers is related to redistribution of fluid from the vascular space into the interstitium. In theory, increased calcium channel blocker-mediated vasodilation leads to increased pressure and subsequent arteriolar permeability in the transcapillary circulation [13]. In one study of 12 healthy subjects, for example, a single dose of nifedipine increased the foot volume despite also increasing sodium excretion [14]. The risk of edema is more common with dihydropyridines than with non-dihydropyridines and appears to be dose dependent. Risk of dihydropyridine-associated edema is two to three times higher with higher than with lower doses of amlodipine [15].

Calcium channel blocker-mediated edema may prompt clinicians to prescribe diuretics, especially loop diuretics, which increase polypharmacy and may cause harm in patients without hypervolemia [16]. However, since calcium channel blocker-mediated edema is not the result of increased plasma volume, it tends not to improve with diuretic therapy [14]. Conversely, addition of an inhibitor of the renin-angiotensin system (RAS), either an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), or a direct renin inhibitor can significantly reduce the incidence and severity of edema caused by calcium channel blockers [17-19]. This effect is probably related to ACE inhibitor- or ARB-mediated venodilation that helps to reduce transcapillary pressure.

As such, edema caused by dihydropyridine calcium channel blockers can be treated by any combination of the following: reduction in dose, switch to a non-dihydropyridine agent, and/or addition of a RAS-blocking agent.

Effects on cardiac function — The non-dihydropyridine calcium channel blockers, verapamil and diltiazem, can diminish cardiac contractility and slow cardiac conduction [12]. As a result, these drugs are relatively contraindicated in patients who are taking beta blockers or who have HFrEF, sick sinus syndrome, and second- or third-degree atrioventricular block.

Use in heart failure and coronary artery disease — Due to their negative inotropic effects, non-dihydropyridine calcium channel blockers should not be used in patients with HFrEF. (See "Calcium channel blockers in heart failure with reduced ejection fraction".)

However, it does appear that both types of calcium channel blockers can be used safely in patients who have heart failure with preserved ejection fraction (HFpEF), and they may also be used in patients with myocardial infarction (MI) and chronic stable angina. (See "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Calcium channel blockers'.)

Use of short-acting dihydropyridines has been demonstrated to cause reflex tachycardia and an increase in sympathetic tone, which may lead to poor outcomes in patients with heart failure and coronary disease. As such, these short-acting agents are generally no longer commercially available (or, if available, seldom used). However, the long-acting dihydropyridines (such as amlodipine, extended-release nifedipine, and felodipine) appear to be safe when used in patients with coronary artery disease or heart failure [20].

PROPOSED BUT UNPROVEN SERIOUS ADVERSE EFFECTS — Several serious adverse effects have been ascribed to calcium channel blockers, although the data supporting these links are weak and inconclusive:

●An increased mortality after acute myocardial infarction (MI) with short-acting but not long-acting agents

●An increased risk for acute MI in hypertensive patients taking short-acting but not long-acting agents

●An increased risk of cancer, particularly breast cancer, although this was not seen in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [21]

●An increased risk of gastrointestinal hemorrhage

Short-acting dihydropyridine calcium channel blockers should generally be avoided. However, long-acting agents, such as felodipine or amlodipine, appear to be safe and effective in treating hypertension and reducing cardiovascular events, including MI.

Possible increased mortality after acute myocardial infarction — Large doses of short-acting nifedipine may increase mortality in patients in the immediate post-MI period [22]. The potential for harm from the profound hypotension and sympathetic activation induced by such large doses of short-acting nifedipine is incontrovertible in these hemodynamically vulnerable patients (table 1). Thus, there is no compelling reason to use short-acting calcium channel blockers in such patients.

Possible increased risk for acute myocardial infarction with short-acting agents — A highly publicized observational study from 1995 suggested that calcium channel blockers increased the risk for an acute MI [23]. Further review suggests that this risk, if it exists, is pertinent only to short-acting dihydropyridines. Multiple randomized, controlled trials involving thousands of hypertensive patients have since found no evidence of increased coronary risk from long-acting calcium channel blockers that do not share the possible harmful cardiovascular effects of the short-acting preparations (table 1).

Possible increased cancer risk — Although some observational studies suggest an association, the balance of data does not support an increased cancer risk among those exposed to calcium channel blockers.

Several observational studies have found an association between calcium channel blockers and an increased risk of cancer [24-26], particularly breast cancer [24]. In a retrospective, case-control study, for example, current and prior use of antihypertensive medications were ascertained from 1907 women diagnosed with breast cancer plus 856 women without breast cancer who were randomly selected from the phone book [24]. Although the use of calcium channel blockers for less than 10 years was not associated with cancer, a subgroup analysis revealed an increased risk of breast cancer among women who used calcium channel blockers for 10 or more years. However, because of the methodologic limitations of this and other observational studies, a causal link between calcium channel blockers and cancer cannot be established based upon these data.

By contrast, a large meta-analysis of antihypertensive medication trials that included more than 300,000 individuals found that calcium channel blockers did not increase the incidence of cancer (odds ratio [OR] 1.05, 95% CI 0.96-1.13) or cancer-related mortality (OR 0.96, 95% CI 0.82-1.11), although the risk of breast cancer, per se, was not analyzed [27]. Additionally, a large, population-based study in the United Kingdom demonstrated no increased risk of overall cancer or breast cancer among people exposed to calcium channel blockers, regardless of duration of exposure [28]. Another large cohort found a lower risk of gastric cancer among those treated with calcium channel blockers [29].

Possible increased gastrointestinal bleeding risk in older adults — Previous observational studies have suggested a possible increased risk of gastrointestinal bleeding with calcium channel blocker use, particularly among older adults. However, these data have not been confirmed in most subsequent reports, including in large, randomized trials (ALLHAT) and meta-analyses.

As an example, in a retrospective analysis of approximately 1000 hypertensive patients among a total of 8000 older adult individuals screened as part of a three-community epidemiologic study, a higher rate of gastrointestinal hemorrhage was observed in those taking short-acting verapamil or diltiazem, but not nifedipine [30]. However, a more complete analysis of available data, including those from clinical trials with amlodipine (including the ALLHAT), suggested that this association was uncertain or unlikely [31]. In addition, a systematic review and meta-analysis of 17 clinical trials demonstrated, at most, a marginal association between calcium channel use and gastrointestinal bleeding, which did not appear to be of important clinical significance [32].

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SUMMARY

●All approved calcium channel blockers inhibit the L-type calcium channel on cells but are divided into two major categories based upon their predominant physiologic effects: the dihydropyridines, which are predominantly vasodilators and have less chronotropic and inotropic effects, and the non-dihydropyridines, which are less potent vasodilators and also slow cardiac contractility and conduction. (See 'Dihydropyridines' above and 'Non-dihydropyridines' above.)

●The potentially adverse effects that may be seen with calcium channel blockers vary with the type and dose.

•The dihydropyridines (eg, amlodipine, felodipine, nifedipine) may lead to headache, lightheadedness, flushing, and dose-dependent peripheral edema in as many as 20 to 30 percent of patients. Edema is related to redistribution of fluid from the vascular space into the interstitium and can be treated by any combination of the following: reduction in dose, switch to a non-dihydropyridine agent, or addition of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). (See 'Edema' above.)

•The major potential adverse effects with the non-dihydropyridines (verapamil and diltiazem) are constipation, which may occur in as many as 25 percent of patients, as well as bradycardia and worsening cardiac output. Due to their negative chronotropic and inotropic effects, non-dihydropyridine calcium channel blockers should not be used in patients taking beta blockers or in those with heart failure and reduced ejection fraction (HFrEF), sick sinus syndrome, or second- or third-degree atrioventricular block. (See 'Effects on cardiac function' above.)

•In addition, chronic use of either dihydropyridines or non-dihydropyridines can lead to gingival hyperplasia in some cases.

●Several serious adverse effects have been ascribed to calcium channel blockers, although the data supporting these links are weak and inconclusive: an increased mortality after acute myocardial infarction (MI) with short-acting but not long-acting agents; an increased risk for acute MI in hypertensive patients taking short-acting but not long-acting agents; an increased risk of cancer, particularly breast cancer; and an increased risk of gastrointestinal hemorrhage. Stronger data indicate that calcium channel blockers do not increase the risk of cancer or gastrointestinal hemorrhage. Thus, short-acting dihydropyridine calcium channel blockers should generally be avoided. However, long-acting agents, such as nifedipine gastrointestinal therapeutic system (GITS) or amlodipine, appear to be safe and effective in treating hypertension and reducing cardiovascular events, including MI but especially stroke. (See 'Proposed but unproven serious adverse effects' above.)